Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

治疗性抑制干性 AMD 中 Fas 介导的视网膜细胞死亡和炎症

基本信息

批准号：
10093659
负责人：
James T Handa
金额：
$ 61.82万
依托单位：
ONL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093659
关键词：
Acute Address Age related macular degeneration Aging Anatomy Antioxidants Atrophic Autophagocytosis Biotechnology Blindness CD95 Antigens Cause of Death Cell Death Cell Survival Cells Cessation of life Chronic Clinical Clinical Research Clinical Trials Data Decision Making Development Disease Disease Progression Dose Effectiveness Exhibits Exposure to Exudative age-related macular degeneration Eye Foundations Fundus Glaucoma Healthcare High Fat Diet Histologic Impairment Individual Inflammation Inflammatory Injections Innovative Therapy Institutes Investments Literature Measures Mediating Microglia Mitochondria Modeling Mus Natural Immunity Nonexudative age-related macular degeneration Oryctolagus cuniculus Outcome Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Peer Review Peptides Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Photoreceptors Proteins Quality of life Reproducibility Retina Retinal Detachment Retinal Diseases Role Safety Schedule Signal Transduction Small Business Technology Transfer Research Social Impacts Societies Solid Stress Structure of retinal pigment epithelium Testing Therapeutic Time Toxicology United States Visual Vitamins Work advanced disease baby boomer biological adaptation to stress cigarette smoke cigarette smoke-induced commercial application commercialization economic impact effective therapy effectiveness testing exposure to cigarette smoke gene therapy geographic atrophy human disease improved inhibitor/antagonist interest intravitreal injection macrophage macula neuroprotection novel phase 2 study preclinical development prevent recruit response retinal damage safety study treatment strategy vector

项目摘要

PROJECT SUMMARY / ABSTRACT Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke (CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function, and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas- mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology company developing innovative therapies that prevent retinal cell death to improve visual outcomes for patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. Phase I of this Fast- track STTR proposal will i) determine the feasibility of using Fas inhibition to protect against acute CS-induced retinal damage, and ii) demonstrate that the duration of inhibition is clinically meaningful. Phase II will test the ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitor. In addition, we will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single intravitreal injection of a Fas inhibitor vector in a novel, peer-reviewed chronic model of atrophic AMD in which apoB100 mice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles human disease. This proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas inhibitors in models of atrophic AMD. Successful execution of the project will support the continued pre-clinical development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company.

项目摘要 /摘要与年龄相关的黄斑变性（AMD）是领导者，并且由于衰老的婴儿潮一代，这是一个日益增长的原因美国不可逆转的视力丧失，与暴露于香烟烟雾密切相关（CS）和高脂饮食（HFD）。虽然有效治疗可用于新血管AMD，但AREDS II 抗氧化剂维生素是中间干AMD的唯一经过验证的治疗方法。不幸的是，aredsii不是对早期或晚期干性疾病有效，并且在中间AMD中，它只是减慢了先进的发展疾病。针对干燥AMD的治疗方法将对受苦的人产生巨大影响，并节省数十亿个每年的医疗保健美元。氧化应激反应的损害，自噬，线粒体功能，以及未折叠的蛋白质反应以及失调的先天免疫与AMD有关，并且因此，已被研究为治疗靶标。最终，这些异常导致视网膜死亡色素上皮（RPE）细胞和感光体（PR），导致永久视力丧失。 FAS介导的细胞死亡是包括AMD在内的许多视网膜疾病中视网膜外细胞损失的主要机制。没有预防FAS介导的AMD中视网膜外细胞死亡的疗法，逻辑治疗策略是防止FAS- 介导的信号传导，无论上游损害如何。 Onl Therapeutics，一种眼科生物技术公司开发创新疗法，以防止视网膜细胞死亡改善视觉效果患者已经证明了FAS抑制在预防视网膜细胞死亡中的有效性 AMD。此外，在急性和青光眼的慢性模型，其中载体提供了明显的内部视网膜神经保护。由于 FA在AMD中的作用以及FAS抑制在眼部压力下保护视网膜中的作用，该提议将检查FAS抑制剂在萎缩AMD的急性和慢性模型中的作用。这个快速的第一阶段跟踪STTR建议i）确定使用FAS抑制以防止急性CS诱导的可行性视网膜损伤，ii）证明抑制持续时间在临床上是有意义的。第二阶段将测试反复玻璃体内注射我们肽FAS抑制剂的眼部安全性和有效性。另外，我们将测试重复玻璃体内注射肽FAS抑制剂的有效性以及一个玻璃体内注射FAS抑制剂载体在新型的，同行评审的萎缩AMD的慢性模型中暴露于CS和HFD的APOB100小鼠开发了与非常相似的地理萎缩表型人类疾病。该建议结合了ONL和Wilmer Eye Institute的专业知识来测试这些FAS 萎缩AMD模型中的抑制剂。该项目的成功执行将支持持续的临床前开发用于干燥AMD的FAS抑制剂，并有助于吸引公司对公司的更多兴趣。